Device for transdermal electrotransport delivery of fentanyl and sufentanil

ABSTRACT

The invention provides an improved electrotransport drug delivery system for analgesic drugs, namely fentanyl and sufentanil. The fentanyl/sufentanil is provided as a water soluble salt (e.g., fentanyl hydrochloride), preferably in a hydrogel formulation, for use in an electrotransport device ( 10 ). In accordance with the present invention, a transdermal electrotransport delivered dose of fentanyl/sufentanil is provided which is sufficient to induce analgesia in (e.g., adult) human patients suffering from moderate-to-severe pain associated with major surgical procedures.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. Ser. No. 09/781,041, filed Feb. 9, 2001,now U.S. Pat. No. 6,425,892, which is a continuation of U.S. Ser. No.08/952,657 filed Mar. 17, 1998, now U.S. Pat. No. 6,216,033, which is a371 of application Ser. No. PCT/US96/07380, filed May 22, 1996, which isa continuation-in-part of U.S. Ser. No. 08/460,785, filed Jun. 5, 1995,now abandoned.

TECHNICAL FIELD

The invention relates generally to improved electrotransport drugdelivery. Specifically, the invention relates to a device, compositionand method for improved electrotransport delivery of analgesic drugs,particularly fentanyl and analogs of fentanyl. A composition is providedin the form of a hydrogel formulation for use in an electrotransportdevice.

BACKGROUND ART

The transdermal delivery of drugs, by diffusion through the epidermis,offers improvements over more traditional delivery methods, such assubcutaneous injections and oral delivery. Transdermal drug deliveryavoids the hepatic first pass effect encountered with oral drugdelivery. Transdermal drug delivery also eliminates patient discomfortassociated with subcutaneous injections. In addition, transdermaldelivery can provide more uniform concentrations of drug in thebloodstream of the patient over time due to the extended controlleddelivery profiles of certain types of transdermal delivery devices. Theterm “transdermal” delivery, broadly encompasses the delivery of anagent through a body surface, such as the skin, mucosa, or nails of ananimal.

The skin functions as the primary barrier to the transdermal penetrationof materials into the body and represents the body's major resistance tothe transdermal delivery of therapeutic agents such as drugs. To date,efforts have been focused on reducing the physical resistance orenhancing the permeability of the skin for the delivery of drugs bypassive diffusion. Various methods for increasing the rate oftransdermal drug flux have been attempted, most notably using chemicalflux enhancers.

Other approaches to-increase the rates of transdermal drug deliveryinclude use of alternative energy sources such as electrical energy andultrasonic energy. Electrically assisted transdermal delivery is alsoreferred to as electrotransport. The term “electrotransport” as usedherein refers generally to the delivery of an agent (e.g., a drug)through a membrane, such as skin, mucous membrane, or nails. Thedelivery is induced or aided by application of an electrical potential.For example, a beneficial therapeutic agent may be introduced into thesystemic circulation of a human body by electrotransport deliverythrough the skin. A widely used electrotransport process,electromigration (also called iontophoresis), involves the electricallyinduced transport of charged ions. Another type of electrotransport,electroosmosis, involves the flow of a liquid, which liquid contains theagent to be delivered, under the influence of an electric field. Stillanother type of electrotransport process, electroporation, involves theformation of transiently-existing pores in a biological membrane by theapplication of an electric field. An agent can be delivered through thepores either passively (i.e., without electrical assistance) or actively(i.e., under the influence of an electric potential). However, in anygiven electrotransport process, more than one of these processes,including at least some “passive” diffusion, may be occurringsimultaneously to a certain extent. Accordingly, the term“electrotransport”, as used herein, should be given its broadestpossible interpretation so that it includes the electrically induced orenhanced transport of at least one agent, which may be charged,uncharged, or a mixture thereof, whatever the specific mechanism ormechanisms by which the agent actually is transported.

Electrotransport devices use at least two electrodes that are inelectrical contact with some portion of the skin, nails, mucousmembrane, or other surface of the body, One electrode, commonly calledthe “donor” electrode, is the electrode from which the agent isdelivered into the body. The other electrode, typically termed the“counter” electrode, serves to close the electrical circuit through thebody. For example, if the agent to be delivered is positively charged,i.e., a cation, then the anode is the donor electrode, while the cathodeis the counter electrode which serves to complete the circuit.Alternatively, if an agent is negatively charged, i.e., an anion, thecathode is the donor electrode and the anode is the counter electrode.Additionally, both the anode and cathode may be considered donorelectrodes if both anionic and cationic agent ions, or if unchargeddissolved agents, are to be delivered.

Furthermore, electrotransport delivery systems generally require atleast one reservoir or source of the agent to be delivered to the body.Examples of such donor reservoirs include a pouch or cavity, a poroussponge or pad, and a hydrophilic polymer or a gel matrix. Such donorreservoirs are electrically connected to, and positioned between, theanode or cathode and the body surface, to provide a fixed or renewablesource of one or more agents or drugs. Electrotransport devices alsohave an electrical power source such as one or more batteries. Typicallyat any one time, one pole of the power source is electrically connectedto the donor electrode, while the opposite pole is electricallyconnected to the counter electrode. Since it has been shown that therate of electrotransport drug delivery is approximately proportional tothe electric current applied by the device, many electrotransportdevices typically have an electrical controller that controls thevoltage and/or current applied through the electrodes, therebyregulating the rate of drug delivery. These control circuits use avariety of electrical components to control the amplitude, polarity,timing, waveform shape, etc. of the electric current and/or voltagesupplied by the power source. See, for example, McNichols et al., U.S.Pat. No. 5,047,007.

To date, commercial transdermal electrotransport drug delivery devices(e.g., the Phoresor, sold by Iomed, Inc. of Salt Lake City, Utah; theDupel Iontophoresis System sold by Empi, Inc. of St. Paul, Minn.; theWebster Sweat Inducer, model 3600, sold by Wescor, Inc. of Logan, Utah)have generally utilized a desk-top electrical power supply unit and apair of skin contacting electrodes. The donor electrode contains a drugsolution while the counter electrode contains a solution of abiocompatible electrolyte salt. The power supply unit has electricalcontrols for adjusting the amount of electrical current applied throughthe electrodes. The “satellite” electrodes are connected to theelectrical power supply unit by long (e.g., 1–2 meters) electricallyconductive wires or cables. The wire connections are subject todisconnection and limit the patient's movement and mobility. Wiresbetween electrodes and controls may also be annoying or uncomfortable tothe patient. Other examples of desk-top electrical power supply unitswhich use “satellite” electrode assemblies are disclosed in Jacobsen etal., U.S. Pat. No. 4,141,359 (see FIGS. 3 and 4); LaPrade, U.S. Pat. No.5,006,108 (see FIG. 9); and Maurer et al., U.S. Pat. No. 5,254,081.

More recently, small self-contained electrotransport delivery deviceshave been proposed to be worn on the skin, sometimes unobtrusively underclothing, for extended periods of time. Such small self-containedelectrotransport delivery devices are disclosed for example in Tapper,U.S. Pat. No. 5,224,927; Sibalis, et al., U.S. Pat. No. 5,224,928; andHaynes et al., U.S. Pat. No. 5,246,418.

There have recently been suggestions to utilize electrotransport deviceshaving a reusable controller which is adapted for use with multipledrug-containing units. The drug-containing units are simply disconnectedfrom the controller when the drug becomes depleted and a freshdrug-containing unit is thereafter connected to the controller. In thisway, the relatively more expensive hardware components of the device(e.g. batteries, LED's, circuit hardware, etc.) can be contained withinthe reusable controller, and the relatively less expensive donorreservoir and counter reservoir matrices can be contained in the singleuse/disposable drug-containing unit, thereby bringing down the overallcost of electrotransport drug delivery. Examples of electrotransportdevices comprised of a reusable controller, removably connected to adrug-containing unit are disclosed in Sage, Jr. et al., U.S. Pat. No.5,320,597; Sibalis, U.S. Pat. No. 5,358,483; Sibalis et al., U.S. Pat.No. 5,135,479 (FIG. 12); and Devane et al., UK Patent Application 2 239803.

In further development of electrotransport devices, hydrogels havebecome particularly favored for use as the drug and electrolytereservoir matrices, in part, due to the fact that water is the preferredliquid solvent for use in electrotransport drug delivery due to itsexcellent biocompatibility compared with other liquid solvents such asalcohols and glycols. Hydrogels have a high equilibrium water contentand can quickly absorb water. In addition, hydrogels tend to have goodbiocompatibility with the skin and with mucosal membranes.

Of particular interest in transdermal delivery is the delivery ofanalgesic drugs for the management of moderate to severe pain. Controlof the rate and duration of drug delivery is particularly important fortransdermal delivery of analgesic drugs to avoid the potential risk ofoverdose and the discomfort of an insufficient dosage.

One class of analgesics that has found application in a transdermaldelivery route is the synthetic opiates, a group of 4-anilinepiperidines. The synthetic opiates, e.g., fentanyl and certain of itsderivatives such as sufentanil, are particularly well-suited fortransdermal administration. These synthetic opiates are characterized bytheir rapid onset of analgesia, high potency, and short duration ofaction. They are estimated to be 80 and 800 times respectively, morepotent than morphine. These drugs are weak bases, i.e., amines, whosemajor fraction is cationic in acidic media.

In an in vivo study to determine plasma concentration, Thysman and Preat(Anesth. Analg. 77 (1993) pp. 61–66) compared simple diffusion offentanyl and sufentanil to electrotransport delivery in citrate bufferat pH 5. Simple diffusion did not produce any detectable plasmaconcentration. The plasma levels attainable depended on the maximum fluxof the drug that can cross the skin and the drug's pharmacokineticproperties, such as clearance and volume of distribution.Electrotransport delivery was reported to have significantly reduced lagtime (i.e., time required to achieve peak plasma levels) as compared topassive transdermal patches (1.5 h versus 14 h). The researchers'conclusions were that electrotransport of these analgesic drugs canprovide more rapid control of pain than classical patches, and a pulsedrelease of drug (by controlling electrical current) was comparable tothe constant delivery of classical patches. See, also, e.g., Thysman etal. Int. J. Pharma., 101 (1994) pp. 105–113; V. Préat et al. Int. J.Pharma., 96 (1993) pp.189–196 (sufentanil); Gourlav et al. Pain, 37(1989) pp. 193–202 (fentanyl); Sebel et al. Eur. J. Clin. Pharmacol. 32(1987) pp. 529–531 (fentanyl and sufentanil). Passive, i.e., bydiffusion, and electrically-assisted transdermal delivery of narcoticanalgesic drugs, such as fentanyl, to induce analgesia, have also bothbeen described in the patent literature. See, for example, Gale et al.,U.S. Pat. No. 4,588,580, and Theeuwes et al., U.S. Pat. No. 5,232,438.

In the last several years, management of post-operative pain has lookedto delivery systems other than electrotransport delivery. Particularattention has been given to devices and systems which permit, withinpredetermined limits, the patient to control the amount of analgesic thepatient receives. The experience with these types of devices hasgenerally been that patient control of the administration of analgesichas resulted in the administration of less analgesic to the patient thanwould have been administered were the dosage prescribed by a physician.Self-administered or patient controlled self-administration has becomeknown (and will be referred to herein) as patient-controlled analgesia(PCA).

Known PCA devices are typically electromechanical pumps which requirelarge capacity electrical power sources, e.g., alternating current ormultiple large capacity battery packs which are bulky. Due to their bulkand complexity, commercially available PCA devices generally require thepatient to be confined to a bed, or some other essentially fixedlocation. Known PCA devices deliver drug to the patient by means of anintravenous line or a catheter which must be inserted into the intendedvein, artery or other organ by a qualified medical technician. Thistechnique requires that the skin barrier be breached in order toadminister the analgesic. (See, Zdeb U.S. Pat. No. 5,232,448). Thus, aspracticed using commercially available PCA devices, PCA requires thepresence of highly skilled medical technicians to initiate and supervisethe operation of the PCA device along with its attendant risk ofinfection. Further, commercially available PCA devices themselves aresomewhat painful to use by virtue of their percutaneous (i.e.,intravenous or subcutaneous) access.

The art has produced little in the way of transdermal electrotransportdevices that can compete with the conventional PCAs in terms of theamount of drug delivered to achieve adequate analgesia and in a patientcontrolled manner. Further, little progress has been made to provide ahydrogel formulation for analgesic electrotransport, particularlyfentanyl transdermal electrotransport delivery, that has long termstability and has performance characteristics comparable to the patientcontrolled electromechanical pumps for, e.g., intravenous delivery ofanalgesic. There is need to provide an analgesic formulation in asuitable device to take advantage of the convenience of electrotransportdelivery in a small, self-contained, patient-controlled device.

DESCRIPTION OF THE INVENTION

The present invention provides a device for improved transdermalelectrotransport delivery of fentanyl and analogs of fentanyl,particularly sufentanil. As such, the device of the present inventionprovides a greater degree of efficiency in electrotransport delivery ofanalgesic fentanyl or sufentanil, concomitantly providing a greatermeasure of patient safety and comfort in pain management. The foregoing,and other advantages of the present invention, are provided by a devicefor delivering fentanyl or sufentanil through a body surface (e.g.,intact skin) by electrotransport, the device having a anodic donorreservoir containing an at least partially aqueous solution of afentanyl/sufentanil salt.

The present invention concerns a device for administering fentanyl orsufentanil by transdermal electrotransport in order to treatmoderate-to-severe pain associated with major surgical procedures. Atransdermal electrotransport dose of about 20 μg to about 60 μg offentanyl, delivered over a delivery interval of up to about 20 minutes,is therapeutically effective in treating moderate-to-severepost-operative pain in human patients having body weights above about 35kg. Preferably, the amount of fentanyl delivered is about 35 μg to about45 μg over a delivery interval of about 5 to 15 minutes, and mostpreferably the amount of fentanyl delivered is about 40 μg over adelivery interval of about 10 minutes. Since fentanyl has a relativelyshort distribution half life once delivered into a human body (i.e.,about 3 hours), the device for inducing analgesia preferably includesmeans for maintaining the analgesia so induced. Thus the device fortransdermally delivering fentanyl by electrotransport preferablyincludes means for delivering at least 1 additional, more preferablyabout 10 to 100 additional, and most preferably about 20 to 80additional, like dose(s) of fentanyl over subsequent like deliveryinterval(s) over a 24 hour period. The ability to deliver multipleidentical doses from a transdermal electrotransport fentanyl deliverydevice also provides the capability of pain management to a widerpatient population, in which different patients require differentamounts of fentanyl to control their pain. By providing the capabilityof administering multiple small transdermal electrotransport fentanyldoses, the patients can titrate themselves to administer only thatamount of fentanyl which is needed to control their pain, and no more.

Other advantages and a fuller appreciation of specific adaptations,compositional variations, and physical attributes of the presentinvention can be learned from an examination of the following drawings,detailed description, examples, and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is hereinafter described in conjunction with theappended drawings, in which:

FIG. 1 is a perspective exploded view of an electrotransport drugdelivery device in accordance with the present invention;

FIG. 2 is a graph illustrating quality of analgesia in patientsadministered with transdermal electrotransport fentanyl as a function oftime; and

FIG. 3 is a graph illustrating pain intensity experienced by patientsadministered transdermal electrotransport fentanyl as a function oftime.

MODES FOR CARRYING OUT THE INVENTION

The present invention provides a fentanyl or sufentanil saltelectrotransport delivery device, and a method of using same, to achievea systemic analgesic effect which is comparable to the effect achievedin known IV accessed patient controlled analgesic pumps. The presentinvention provides an electrotransport delivery device for deliveringfentanyl or sufentanil through a body surface, e.g., skin, to achievethe analgesic effect. The fentanyl or sufentanil salt is provided in adonor reservoir of an electrotransport delivery device, preferably as anaqueous salt solution.

The dose of fentanyl delivered by transdermal electrotransport is about20 μg to about 60 μg over a delivery time of up to about 20 minutes inhuman patients having body weights of 35 kg or greater. Preferred is adosage of about 35 μg to about 45 μg, and most preferred is a dosage ofabout 40 μg for the delivery period. The device of the invention furtherpreferably includes means for delivering about 10 to 100, and morepreferably about 20 to 80 additional like doses over a period of 24hours in order to achieve and maintain the analgesic effect.

The dose of sufentanil delivered by transdermal electrotransport isabout 2.3 μg to about 7.0 μg over a delivery time of up to about 20minutes in human patients having a body weights of 35 kg or greater.Preferred is a dosage of about 4 μg to about 5.5 μg, and most preferredis a dosage of about 4.7 μg for the delivery period. The device of theinvention further preferably includes means for delivering about 10 to100, and more preferably about 20 to 80 additional like doses over aperiod of 24 hours in order to achieve and maintain the analgesiceffect.

The fentanyl/sufentanil salt-containing anodic reservoir formulation fortransdermally delivering the above mentioned doses offentanyl/sufentanil by electrotransport is preferably comprised of anaqueous solution of a water soluble fentanyl/sufentanil salt such as HClor citrate salts. Most preferably, the aqueous solution is containedwithin a hydrophilic polymer matrix such as a hydrogel matrix. Thefentanyl/sufentanil salt is present in an amount sufficient to deliverthe above mentioned doses transdermally by electrotransport over adelivery period of up to about 20 minutes, to achieve a systemicanalgesic effect. The fentanyl/sufentanil salt typically comprises about1 to 10 wt % of the donor reservoir formulation (including the weight ofthe polymeric matrix) on a fully hydrated basis, and more preferablyabout 1 to 5 wt % of the donor reservoir formulation on a fully hydratedbasis. Although not critical to this aspect of the present invention,the applied electrotransport current density is typically in the rangeof about 50 to 150 μA/cm² and the applied electrotransport current istypically in the range of about 150 to 240 μA.

The anodic fentanyl/sufentanil salt-containing hydrogel can suitably bemade of a any number of materials but preferably is comprised of ahydrophilic polymeric material, preferably one that is polar in natureso as to enhance the drug stability. Suitable polar polymers for thehydrogel matrix comprise a variety of synthetic and naturally occurringpolymeric materials. A preferred hydrogel formulation contains asuitable hydrophilic polymer, a buffer, a humectant, a thickener, waterand a water soluble fentanyl or sufentanil salt (e.g., HCl salt). Apreferred hydrophilic polymer matrix is polyvinyl alcohol such as awashed and fully hydrolyzed polyvinyl alcohol (PVOH), e.g., Mowiol66–100 commercially available from Hoechst Aktiengesellschaft. Asuitable buffer is an ion exchange resin which is a copolymer ofmethacrylic acid and divinylbenzene in both an acid and salt form. Oneexample of such a buffer is a mixture of Polacrilin (the copolymer ofmethacrylic acid and divinyl benzene available from Rohm & Haas,Philadelphia, Pa.) and the potassium salt thereof. A mixture of the acidand potassium salt forms of Polacrilin functions as a polymeric bufferto adjust the pH of the hydrogel to about pH 6. Use of a humectant inthe hydrogel formulation is beneficial to inhibit the loss of moisturefrom the hydrogel. An example of a suitable humectant is guar gum.Thickeners are also beneficial in a hydrogel formulation. For example, apolyvinyl alcohol thickener such as hydroxypropyl methylcellulose (e.g.,Methocel K100 MP available from Dow Chemical, Midland, Mich.) aids inmodifying the rheology of a hot polymer solution as it is dispensed intoa mold or cavity. The hydroxypropyl methylcellulose increases inviscosity on cooling and significantly reduces the propensity of acooled polymer solution to overfill the mold or cavity.

In one preferred embodiment, the anodic fentanyl/sufentanilsalt-containing hydrogel formulation comprises about 10 to 15 wt %polyvinyl alcohol, 0.1 to 0.4 wt % resin buffer, and about 1 to 2 wt %fentanyl or sufentanil salt, preferably the hydrochloride salt. Theremainder is water and ingredients such as humectants, thickeners, etc.The polyvinyl alcohol (PVOH)-based hydrogel formulation is prepared bymixing all materials, including the fentanyl or sufentanil salt, in asingle vessel at elevated temperatures of about 90° C. to 95° C. for atleast about 0.5 hr. The hot mix is then poured into foam molds andstored at freezing temperature of about −35° C. overnight to cross-linkthe PVOH. Upon warming to ambient temperature, a tough elastomeric gelis obtained suitable for fentanyl electrotransport.

The hydrogel formulations are used in an electrotransport device such asdescribed hereinafter. A suitable electrotransport device includes ananodic donor electrode, preferably comprised of silver, and a cathodiccounter electrode, preferably comprised of silver chloride. The donorelectrode is in electrical contact with the donor reservoir containingthe aqueous solution of a fentanyl/sufentanil salt. As described above,the donor reservoir is preferably a hydrogel formulation. The counterreservoir also preferably comprises a hydrogel formulation containing a(e.g., aqueous) solution of a biocompatible electrolyte, such as citratebuffered saline. The anodic and cathodic hydrogel reservoirs preferablyeach have a skin contact area of about 1 to 5 cm² and more preferablyabout 2 to 3 cm². The anodic and cathodic hydrogel reservoirs preferablyhave a thickness of about 0.05 to 0.25 cm, and more preferably about0.15 cm. The applied electrotransport current is about 150 μA to about240 μA, depending on the analgesic effect desired. Most preferably, theapplied electrotransport current is substantially constant DC currentduring the dosing interval.

Reference is now made to FIG. 1 which depicts an exemplaryelectrotransport device which can be used in accordance with the presentinvention. FIG. 1 shows a perspective exploded view of anelectrotransport device 10 having an activation switch in the form of apush button switch 12 and a display in the form of a light emittingdiode (LED) 14. Device 10 comprises an upper housing 16, a circuit boardassembly 18, a lower housing 20, anode electrode 22, cathode electrode24, anode reservoir 26, cathode reservoir 28 and skin-compatibleadhesive 30. Upper housing 16 has lateral wings 15 which assist inholding device 10 on a patient's skin. Upper housing 16 is preferablycomposed of an injection moldable elastomer (e.g., ethylene vinylacetate). Printed circuit board assembly 18 comprises an integratedcircuit 19 coupled to discrete electrical components 40 and battery 32.Circuit board assembly 18 is attached to housing 16 by posts (not shownin FIG. 1) passing through openings 13 a and 13 b, the ends of the postsbeing heated/melted in order to heat stake the circuit board assembly 18to the housing 16. Lower housing 20 is attached to the upper housing 16by means of adhesive 30, the upper surface 34 of adhesive 30 beingadhered to both lower housing 20 and upper housing 16 including thebottom surfaces of wings 15.

Shown (partially) on the underside of circuit board assembly 18 is abattery 32, which is preferably a button cell battery and mostpreferably a lithium cell. Other types of batteries may also be employedto power device 10.

The circuit outputs (not shown in FIG. 1) of the circuit board assembly18 make electrical contact with the electrodes 24 and 22 throughopenings 23,23′ in the depressions 25,25′ formed in lower housing, bymeans of electrically conductive adhesive strips 42,42′. Electrodes 22and 24, in turn, are in direct mechanical and electrical contact withthe top sides 44′,44 of reservoirs 26 and 28. The bottom sides 46′,46 ofreservoirs 26,28 contact the patient's skin through the openings 29′,29in adhesive 30. Upon depression of push button switch 12, the electroniccircuitry on circuit board assembly 18 delivers a predetermined DCcurrent to the electrodes/reservoirs 22,26 and 24,28 for a deliveryinterval of predetermined length, e.g., about 10 minutes. Preferably,the device transmits to the user a visual and/or audible confirmation ofthe onset of the drug delivery, or bolus, interval by means of LED 14becoming lit and/or an audible sound signal from, e.g., a “beeper”.Analgesic drug, e.g. fentanyl, is then delivered through the patient'sskin, e.g., on the arm, for the predetermined (e.g., 10 minute) deliveryinterval. In practice, a user receives feedback as to the onset of thedrug delivery interval by visual (LED 14 becomes lit) and/or audiblesignals (a beep from the “beeper”).

Anodic electrode 22 is preferably comprised of silver and cathodicelectrode 24 is preferably comprised of silver chloride. Both reservoirs26 and 28 are preferably comprised of polymer hydrogel materials asdescribed herein. Electrodes 22, 24 and reservoirs 26, 28 are retainedby lower housing 20. For fentanyl and sufentanil salts, the anodicreservoir 26 is the “donor” reservoir which contains the drug and thecathodic reservoir 28 contains a biocompatible electrolyte.

The push button switch 12, the electronic circuitry on circuit boardassembly 18 and the battery 32 are adhesively “sealed” between upperhousing 16 and lower housing 20. Upper housing 16 is preferably composedof rubber or other elastomeric material. Lower housing 20 is preferablycomposed of a plastic or elastomeric sheet material (e.g., polyethylene)which can be easily molded to form depressions 25,25′ and cut to formopenings 23,23′. The assembled device 10 is preferably water resistant(i.e., splash proof and is most preferably waterproof. The system has alow profile that easily conforms to the body thereby allowing freedom ofmovement at, and around, the wearing site. The anode/drug reservoir 26and the cathode/salt reservoir 28 are located on the skin-contactingside of device 10 and are sufficiently separated to prevent accidentalelectrical shorting during normal handling and use.

The device 10 adheres to the patient's body surface (e.g., skin) bymeans of a peripheral adhesive 30 which has upper side 34 andbody-contacting side 36. The adhesive side 36 has adhesive propertieswhich assures that the device 10 remains in place on the body duringnormal user activity, and yet permits reasonable removal after thepredetermined (e.g., 24-hour) wear period. Upper adhesive side 34adheres to lower housing 20 and retains the electrodes and drugreservoirs within housing depressions 25,25′ as well as retains lowerhousing 20 attached to upper housing 16.

The push button switch 12 is located on the top side of device 10 and iseasily actuated through clothing. A double press of the push buttonswitch 12 within a short period of time, e.g., three seconds, ispreferably used to activate the device 10 for delivery of drug, therebyminimizing the likelihood of inadvertent actuation of the device 10.

Upon switch activation an audible alarm signals the start of drugdelivery, at which time the circuit supplies a predetermined level of DCcurrent to the electrodes/reservoirs for a predetermined (e.g., 10minute) delivery interval. The LED 14 remains “on” throughout thedelivery interval indicating that the device 10 is in an active drugdelivery mode. The battery preferably has sufficient capacity tocontinuously power the device 10 at the predetermined level of DCcurrent for the entire (e.g., 24 hour) wearing period.

Preferably, the concentration of fentanyl or sufentanil in solution inthe donor reservoir is maintained at or above the level at which thetransdermal electrotransport fentanyl/sufentanil flux is independent ofdrug concentration in the donor reservoir during the electrotransportdrug delivery period. Transdermal electrotransport fentanyl flux beginsto become dependent upon the concentration of the fentanyl salt inaqueous solution as the fentanyl salt concentration falls below about 11to 16 mM. The 11 to 16 mM concentration is calculated based only on thevolume of liquid solvent used in the donor reservoir, not on the totalvolume of the reservoir. In other words, the 11 to 16 mM concentrationdoes not include the volume of the reservoir which is represented by thereservoir matrix (e.g., hydrogel or other matrix) material. Furthermore,the 11 to 16 mM concentration is based upon the number of moles offentanyl salt, not the equivalent number of moles of fentanyl free base,which is contained in the donor reservoir solution. For fentanyl HCl,the 11 to 16 mM concentration is equivalent to about 4 to 6 mg/mL. Otherfentanyl salts (e.g., fentanyl citrate) will have slightly differingweight based concentration ranges based on the difference in themolecular weight of the counter ion of the particular fentanyl salt inquestion. As the fentanyl salt concentration falls to about 11 to 16 mM,the fentanyl transdermal electrotransport flux begins to significantlydecline, even if the applied electrotransport current remains constant.Thus, to ensure a predictable fentanyl flux with a particular level ofapplied electrotransport current, the fentanyl salt concentration in thesolution contained in the donor reservoir is preferably maintained aboveabout 11 mM, and more preferably above about 16 mM. In addition tofentanyl, water soluble salts of sufentanil also have minimum aqueoussolution concentrations below which the transdermal electrotransportflux becomes dependent on concentration of the sufentanil salt insolution. The minimum concentration for sufentanil is about 1.7 mM,which for sufentanil citrate is equivalent to about 1 mg/mL.

Since fentanyl and sufentanil are both bases, the salts of fentanyl andsufentanil are typically acid addition salts, e.g., citrate salts,hydrochloride salts, etc. The acid-addition-salts of fentanyl typicallyhave water solubilities of about 25 to 30 mg/mL. The acid addition saltsof sufentanil typically have water solubilities of about 45 to 50 mg/mL.When these salts are placed in solution (e.g., aqueous solution), thesalts dissolve and form protonated fentanyl or sufentanil cations andcounter (e.g., citrate or chloride) anions. As such, thefentanyl/sufentanil cations are delivered from the anodic electrode ofan electrotransport delivery device. Silver anodic electrodes have beenproposed for transdermal electrotransport delivery as a way to maintainpH stability in the anodic reservoir. See for example, Untereker et alU.S. Pat. No. 5,135,477 and Petelenz et al U.S. Pat. No. 4,752,285.These patents also recognize one of the shortcomings of using a silveranodic electrode in an electrotransport delivery device, namely that theapplication of current through the silver anode causes the silver tobecome oxidized (Ag→Ag⁺+e⁻) thereby forming silver cations which competewith the cationic drug for delivery into the skin by electrotransport.Silver ion migration into the skin results in a transient epidermaldiscoloration (TED) of the skin. In accordance with the teachings inthese patents, the cationic fentanyl and sufentanil are preferablyformulated as a halide salt (e.g., hydrochloride salt) so that anyelectrochemically-generated silver ions will react with the drug counterions (i.e., halide ions) to form a substantially insoluble silver halide(Ag⁺+X⁻→AgX). In addition to these patents, Phipps et al, WO 95/27530teaches the use of supplementary chloride ion sources in the form ofhigh molecular weight chloride resins in the donor reservoir of atransdermal electrotransport delivery device. These resins are highlyeffective at providing sufficient chloride for preventing silver ionmigration, and the attendant skin discoloration when delivering fentanylor sufentanil transdermally by electrotransort using a silver anodicelectrode.

The present invention is further explained by the following exampleswhich illustrative of, but do not limit the scope of, the presentinvention.

EXAMPLE 1

The following studies were conducted to determine the transdermalelectrotransport dosing level required to achieve an acceptable level ofanalgesia in human patients suffering from moderate to severepost-operative pain. The study was conducted in 132 post-operative maleand female patients who were expected to have moderate to severe painafter surgery, including orthopedic (shoulder, knee, long bone) andabdominal (urological, gynecological) surgeries. The patients wore oneof two different electrotransport fentanyl HCl delivery devices on theupper arm for 24 hours following surgery. Both devices appliedelectrotransport current for a delivery interval of 10 minutes uponactivating a push button switch on the device. The first device, worn by79 of the 132 patients, applied an electrotransport current of 150 μAwhich delivered an average fentanyl dose of 25 μg over the 10 minutedelivery interval. The second device, worn by 53 of the 132 patients,applied an electrotransport current of 240 μA which delivered an averagefentanyl dose of 40 μg over the 10 minute delivery interval.

In both devices, the patients could self-administer up to 6 doses everyhour. Patients using the first (i.e., 25 μg dose) device could apply amaximum of 144 doses. Patients using the second (i.e., 40 μg dose)device were allowed to apply up to a maximum number of 80 doses.

Both devices were two-part systems which included a reusable electroniccontroller and a single use/disposable drug-containing unit. Each drugunit contained an anodic fentanyl HCl-containing donor gel and acathodic saline-containing counter gel. All gels had a skin contact areaof 2 cm² and a thickness of 0.16 cm. The approximate weight of the donorgels was 350 mg. The anodic donor gels in the 25 μg dose and 40 μg dosesystems were the same size and composition, only the appliedelectrotransport current level was different. The cathodic counterelectrode assemblies each had a PVOH based gel which contained citratebuffered saline. A silver chloride cathodic electrode was laminated toone surface of the counter gel. The 25 μg and 40 μg dose anodic gels hadthe following composition:

Material (wt %) Water 73.2 PVOH 10.0 Fentanyl HCl 1.4 Polacrilin 0.3Polacrilin potassium 0.1 Glycerin 5.0 Cholestyramine resin 10.0

All patients were initially titrated to an acceptable level of analgesiawith intravenous (IV) fentanyl in the recovery room immediatelyfollowing surgery. Within 3 hours after surgery when the patients hadmet the usual institutional standards for discharge from the recoveryroom and were able to operate their worn electrotransport deliverydevice, the patients were moved to a ward where they could selfadminister fentanyl by transdermal electrotransport for the managementof their pain. In the event the electrotransport fentanyl deliveryregimen was insufficient to control pain, the patients were retitratedwith supplemental fentanyl through IV administration to achieve adequateanalgesia.

In the 25 μg dose group, 38 of 79 patients (i.e., 48%) required nosupplemental IV fentanyl after leaving the recovery room. In the 40 μgdose group, 47 of 53 patients (i.e., 89%) required no supplemental IVfentanyl after leaving the recovery room. Based on these percentages, itwas determined that the 25 μg dose regimen was sufficient to treat thepain associated with these types of surgical procedures in aboutone-half of the patients; and the 40 μg dose regimen was sufficient totreat the pain associated with these types of surgical procedures inabout 90% of the patients tested. Because the 25 μg dose regimen wasanalgesically effective for about half the patients, lower dosingregimens of about 20 to 30 μg and preferably about 20 to 25 μg offentanyl over these same dosing intervals (i.e., up to 20 minutes) arealso effective, and less susceptible to unintentional over-dosing, intreating less severe acute pain such as that experienced with herniarepair, kidney stones, arthritis pain, laparascopic procedures, andother conditions involving less severe pain than that associated withmajor surgeries. The corresponding lower dosing regimens for sufentanilare about 2.3 μg to about 3.5 μg, and preferably about 2.3 μg to about2.9 μg, delivered over these same dosing intervals (i.e., up to 20minutes).

Pain intensity was assessed at baseline immediately before activation ofthe first on-demand dose and again at times 0.5, 1, 2, 3, 4, 6, 8, 12,16, 20 and 24 hours after the devices were first activated. The patientswere asked to assess pain intensity by marking on a 10 cm long strip,containing a scale of 1 to 100, with 1 being associated with no pain and100 being associated with the most severe intensity pain. The quality ofanalgesia was evaluated by a categorical rating of excellent, good, fairor unsatisfactory according to the same time schedule as that for thepain intensity measurements.

The quality of analgesia and pain intensity data for the 53 patientsusing the 40 μg dose electrotransport devices are shown in FIGS. 2 and3, respectively.

Skin sites beneath the anode and cathode gels were assessed at 1, 6 and24 hours following removal of the devices and evaluated for topical(e.g., irritation) effects. The topical effects data are shown in Table1

TABLE 1 Hours ETS Extent of Post Skin Edema Erythema Erythema ItchingPapules Pustules Removal Site Score (%) (%) (%) (%) (%) (%) 1 Anode 0 7415 19 91 92 100 1 8 49 32 6 6 0 2 19 36 49 4 2 0 Cathode 0 92 72 74 9494 100 1 6 19 13 4 6 0 2 2 9 13 2 0 0 6 Anode 0 74 15 17 89 92 100 1 1143 34 8 8 0 2 15 40 49 4 0 0 3 0 2 0 0 0 0 Cathode 0 92 68 68 91 91 1001 4 19 13 9 6 0 2 4 9 19 0 4 0 3 0 4 0 0 0 0 24 Anode 0 83 34 36 91 9698 1 9 40 38 8 4 2 2 8 26 36 2 0 0 3 0 0 0 0 0 0 Cathode 0 91 70 70 9189 98 1 6 19 15 8 8 0 2 4 8 15 2 4 2 3 0 4 0 0 0 0 Erythema: 0 = None 1= Barely perceptible redness 2 = Definite redness 3 = “Beet” rednessItching: 0 = None 1 = Mild 2 = Moderate 3 = Severe Edema, Papules,Pustules, Extent of Erythema: 0 = None 1 = <50% of occluded area 2= >50% of occluded area

EXAMPLE 2

Two fentanyl hydrochloride-containing anodic donor reservoir PVOH-basedgels were made having the following compositions:

Donor Gel Formulations: Material wt % wt % Purified Water 86.3 85.3Washed PVOH 12.0 12.0 Fentanyl HCl  1.7 1.7 Hydroxy Methylcellulose —1.0

With both formulations, the water and PVOH are mixed at a temperaturebetween 92° C. and 98° C. followed by the addition of fentanylhydrochloride and subsequent further mixing. The liquid gel was thenpumped into foam molds having a disc-shaped cavity. The molds wereplaced in a freezer overnight at −35° C. to cross-link the PVOH. Thegels can be used as anodic donor reservoirs suitable for transdermalelectrotransport fentanyl delivery to achieve patient analgesia.

In summary, the present invention provides a device for improving thetransdermal electrotransport of water soluble salts of fentanyl andsufentanil. The electrotransport device preferably has a silver anodicdonor electrode and a hydrogel based donor reservoir. Theelectrotransport device is preferably a patient-controlled device. Thehydrogel formulation contains a drug concentration which is sufficientto provide an acceptable level of analgesia.

1. A method of obtaining analgesia in a human patient who is sufferingfrom pain, consisting of transdermally delivering solely byelectrotransport a dose of about 20 micrograms to about 60 micrograms offentanyl over a predetermined delivery period of up to about 20 minutes,terminating said delivery at the end of said delivery period andthereafter repeating such transdermal administering up to about 100additional of said doses over a period of about 24 hours, wherein theapplied electrotransport current density is in the range of about 50 toabout 150 microamps per square centimeter.
 2. The method of claim 1,wherein about 35 micrograms to about 45 micrograms of fentanyl isdelivered over a delivery period of about 5 to 15 minutes.
 3. The methodof claim 1, wherein about 40 micrograms of fentanyl is delivered overthe delivery period.
 4. The method of claim 1, wherein the deliveryperiod is about 10 minutes.
 5. The method of claim 1, wherein theadditional doses are 35 micrograms to 45 micrograms doses of fentanyl.6. The method of claim 1, wherein the fentanyl comprises a fentanylsalt.
 7. The method of claim 6, wherein the fentanyl salt comprisesfentanyl hydrochloride.
 8. The method of claim 1, wherein the doses areself-administered by the patient suffering from pain.
 9. The method ofclaim 8, wherein the patient is allowed to self-administer no more thansix of said doses per hour.